Discovery points to potential mechanism of cancer drug resistance
US scientists have identified a potentially important escape mechanism for tumour cells that may help them dodge certain targeted drugs.
"Drug resistance is a big challenge for doctors and patients alike, and something many researchers are trying to understand." - Dr John Brognard, Cancer Research UK
The team at the University of California in San Francisco (UCSF) found that a molecule called YAP plays a key role in the emergence of resistance to targeted cancer therapies, demonstrating how some drugs lose effectiveness.
They hope that identifying how high levels of the protein helps cancer cells survive could lead to new combination therapies to overcome resistance to individual targeted drugs.
So far results have only been shown in cells grown in the lab and in mice, but could pave the way for promising further studies.
Dr John Brognard, an expert in cell signalling at Cancer Research UK, acknowledged the promise of this study, but stressed there was still more work to be done.
“This preliminary but compelling study identifies a potentially important escape mechanism that some tumour cells may rely on as they become resistant to particular targeted cancer treatments. Drug resistance is a big challenge for doctors and patients alike, and something many researchers are trying to understand,” he said.
The research, published in the journal Nature Genetics, focussed on cancer cells that were resistant to a drug that targets a faulty version of the BRAF gene.
The team used a genetic trick to switch off the production of 5,000 different proteins one-by-one in the cancer cells while treating them with a BRAF targeting drug called vemurafenib.
Here the team landed on YAP, showing that high levels of the protein inside cancer cells may shield the cells from drug-induced death. They also saw the same effects in cells treated with a different drug that targets another gene called MEK.
Combining the drugs – vemurafenib thats targets RAF or trametinib that targets MEK – with a block in YAP production made them far more effective compared to when administered alone in mice.
The provisional conclusion is that a combined therapy targeting YAP could help overcome resistance to these targeted therapies.
Dr Trever Bivona, UCSF assistant professor of medicine and a member of the UCSF Helen Diller Family Comprehensive Cancer Center, said: "We want to learn how to wipe out that alternative survival pathway at the beginning of therapy – to pull the rug out from under those cells right away."
But Brognard was quick to caution that this approach has a number of challenges to overcome.
“These results have so far only been shown in cells grown in the lab and in mice. And while preliminary results suggest that the mechanism may also be active in patient samples, further research will need to focus on confirming this. And even if they do, there are also technical challenges to be overcome in designing drugs to switch off the protein involved - called YAP - in patients’ tumours,” he said.